Associations of hyperglycemia and insulin usage with the risk of cancer in type 2 diabetes: the Hong Kong diabetes registry

Xilin Yang, Gary T C Ko, Wing Yee So, Ronald C W Ma, Linda W L Yu, Alice P S Kong, Hailu Zhao, Chun-Chung Chow, Peter C Y Tong, Juliana C N Chan, Xilin Yang, Gary T C Ko, Wing Yee So, Ronald C W Ma, Linda W L Yu, Alice P S Kong, Hailu Zhao, Chun-Chung Chow, Peter C Y Tong, Juliana C N Chan

Abstract

OBJECTIVE Insulin has mitogenic effects, although hyperglycemia may be a risk factor for cancer in type 2 diabetes. It remains uncertain whether use of insulin increases cancer risk because of its effect on cell growth and proliferation or decreases cancer risk because of its glucose-lowering effect. RESEARCH DESIGN AND METHODS A 1:2-matched new insulin user cohort on age (+/-3 years), smoking status, and likelihood of initiating insulin therapy (+/-0.05) was selected from a cohort of 4,623 Chinese patients with type 2 diabetes, free of cancer, and naive to insulin at enrollment. Stratified Cox regression analysis on the matched pairs was used to obtain hazard ratios (HRs) of insulin therapy and A1C for cancer risk. A structured adjustment scheme was used to adjust for covariates. RESULTS Of 973 new insulin users, 971 had matched nonusers (n = 1935). The cancer incidence in insulin nonusers was much higher than that in insulin users (49.2 vs. 10.2, per 1,000 person-years, P < 0.0001). After further adjustment for all other covariates with a P value less than 0.3 and nonlinear associations with cancer, A1C was associated with an increased cancer risk (HR per percentage 1.26, 95% CI 1.03-1.55), whereas use of insulin was associated with a decreased cancer risk (HR of insulin users vs. nonusers: 0.17, 0.09-0.32). Consistent results were found in analyses including all 973 insulin users and 3,650 nonusers. CONCLUSIONS In Chinese patients with type 2 diabetes, hyperglycemia predicts cancer, whereas insulin usage was associated with a reduced cancer risk.

Figures

FIG. 1.
FIG. 1.
Patient flow chart. Adjusted for use of insulin during follow-up period, and covariates as listed in the adjustment scheme of model 3 in Table 3 plus matching criteria (i.e., age, smoking status, and probability of using insulin during follow-up period).
FIG. 2.
FIG. 2.
Hazard ratio of A1C for incident cancer in the cohort of 4,623 Chinese patients with type 2 diabetes.

References

    1. Straus DS. Growth-stimulatory actions of insulin in vitro and in vivo. Endocr Rev 1984;5:356–369
    1. Kim YI. Diet, lifestyle, and colorectal cancer: is hyperinsulinemia the missing link? Nutr Rev 1998;56:275–279
    1. LeRoith D, Novosyadlyy R, Gallagher EJ, Lann D, Vijayakumar A, Yakar S. Obesity and type 2 diabetes are associated with an increased risk of developing cancer and a worse prognosis; epidemiological and mechanistic evidence. Exp Clin Endocrinol Diabetes 2008;116(Suppl 1.):S4–S6
    1. Gunter MJ, Hoover DR, Yu H, Wassertheil-Smoller S, Rohan TE, Manson JE, Li J, Ho GY, Xue X, Anderson GL, Kaplan RC, Harris TG, Howard BV, Wylie-Rosett J, Burk RD, Strickler HD. Insulin, insulin-like growth factor-I, and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 2009;101:48–60
    1. Hemkens LG, Grouven U, Bender R, Günster C, Gutschmidt S, Selke GW, Sawicki PT. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia 2009;52:1732–1744
    1. Jonasson JM, Ljung R, Talbäck M, Haglund B, Gudbjörnsdòttir S, Steineck G. Insulin glargine use and short-term incidence of malignancies-a population-based follow-up study in Sweden. Diabetologia 2009;52:1745–1754
    1. Colhoun HMSDRN Epidemiology Group. Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia 2009;52:1755–1765
    1. Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 2009;52:1766–1777
    1. Smith U, Gale EA. Does diabetes therapy influence the risk of cancer? Diabetologia 2009;52:1699–1708
    1. Rosenstock J, Fonseca V, McGill JB, Riddle M, Hallé JP, Hramiak I, Johnston P, Davis M. Similar risk of malignancy with insulin glargine and neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes: findings from a 5 year randomised, open-label study. Diabetologia 2009;52:1971–1973
    1. Garg SK, Hirsch IB, Skyler JS. Insulin glargine and cancer: an unsubstantiated allegation. Diabetes Technol Ther 2009;11:473–476
    1. Saydah SH, Platz EA, Rifai N, Pollak MN, Brancati FL, Helzlsouer KJ. Association of markers of insulin and glucose control with subsequent colorectal cancer risk. Cancer Epidemiol Biomarkers Prev 2003;12:412–418
    1. Stattin P, Björ O, Ferrari P, Lukanova A, Lenner P, Lindahl B, Hallmans G, Kaaks R. Prospective study of hyperglycemia and cancer risk. Diabetes Care 2007;30:561–567
    1. Best JD, O'Neal DN. Diabetic dyslipidaemia: current treatment recommendations. Drugs 2000;59:1101–1111
    1. Yang X, So W, Ko GT, Ma RC, Kong AP, Chow CC, Tong PC, Chan JC. Independent associations between low-density lipoprotein cholesterol and cancer among patients with type 2 diabetes mellitus. CMAJ 2008;179:427–437
    1. Yang X, So WY, Ma RC, Ko GT, Kong AP, Wang Q, Cockram CS, Chow CC, Chan JC, Tong PC. Predicting values of lipids and white blood cell count for all-site cancer in type 2 diabetes. Endocr Relat Cancer 2008;15:597–607
    1. Chen J, Li D, Schaefer R, Mehta JL. Cross-talk between dyslipidemia and renin-angiotensin system and the role of LOX-1 and MAPK in atherogenesis studies with the combined use of rosuvastatin and candesartan. Atherosclerosis 2006;184:295–301
    1. Chen J, Mehta JL. Interaction of oxidized low-density lipoprotein and the renin-angiotensin system in coronary artery disease. Curr Hypertens Rep 2006;8:139–143
    1. Yang X, Zhao H, Sui Y, Ma RC, So WY, Ko GT, Kong AP, Ozaki R, Yeung CY, Xu G, Tong PC, Chan JC. Additive interaction between the renin-angiotensin system and lipid metabolism for cancer in type 2 diabetes. Diabetes 2009;58:1518–1525
    1. Liguori A, Abete P, Hayden JM, Cacciatore F, Rengo F, Ambrosio G, Bonaduce D, Condorelli M, Reaven PD, Napoli C. Effect of glycaemic control and age on low-density lipoprotein susceptibility to oxidation in diabetes mellitus type 1. Eur Heart J 2001;22:2075–2084
    1. Piwernetz K, Home PD, Snorgaard O, Antsiferov M, Staehr-Johansen K, Krans M. Monitoring the targets of the St Vincent Declaration and the implementation of quality management in diabetes care: the DIABCARE initiative: The DIABCARE Monitoring Group of the St Vincent Declaration Steering Committee. Diabet Med 1993;10:371–377
    1. Yang X, So WY, Tong PC, Ma RC, Kong AP, Lam CW, Ho CS, Cockram CS, Ko GT, Chow CC, Wong VC, Chan JC. Development and validation of an all-cause mortality risk score in type 2 diabetes–The Hong Kong Diabetes Registry. Arch Intern Med 2008;168:451–457
    1. So WY, Yang X, Ma RC, Kong AP, Lam CW, Ho CS, Cockram CS, Ko GT, Chow CC, Wong V, Tong PC, Chan JC. Risk factors in V-shaped risk associations with all-cause mortality in type 2 diabetes–The Hong Kong Diabetes Registry. Diabetes Metab Res Rev 2008;24:238–246
    1. Ray WA. Evaluating medication effects outside of clinical trials: new-user designs. Am J Epidemiol 2003;158:915–920
    1. Ma YC, Zuo L, Chen JH, Luo Q, Yu XQ, Li Y, Xu JS, Huang SM, Wang LN, Huang W, Wang M, Xu GB, Wang HY. Modified glomerular filtration rate estimating equation for Chinese patients with chronic kidney disease. J Am Soc Nephrol 2006;17:2937–2944
    1. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499–502
    1. Yang X, So WY, Ma RC, Ko GT, Kong AP, Zhao H, Luk AO, Lam CW, Ho CS, Tong PC, Chan JC. Low LDL cholesterol, albuminuria, and statins for the risk of cancer in type 2 diabetes: the Hong Kong diabetes registry. Diabetes Care 2009;32:1826–1832
    1. Harrell F. Regression Modelling Strategies with Applications to Linear Models, Logistic Regression, and Survival Analysis. New York, NY, Spinger-Varlag, 2001
    1. Yang X, Ko GT, So WY, Ma RC, Kong AP, Lam CW, Ho CS, Chow CC, Tong PC, Chan JCHong Kong Diabetes Registry. Additive interaction of hyperglycemia and albuminuria on risk of ischemic stroke in type 2 diabetes: Hong Kong Diabetes Registry. Diabetes Care 2008;31:2294–2300
    1. Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 2009;32:1620–1625
    1. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ 2005;330:1304–1305
    1. Feinstein AR. Clinical biostatistics: XI, sources of ‘chronology bias’ in cohort statistics. Clin Pharmacol Ther 1971;12:864–879
    1. Pintilie M. Dealing with competing risks: testing covariates and calculating sample size. Stat Med 2002;21:3317–3324

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